Osteoarthritis (OA), the most common form of arthritis, is a prevalent and debilitating disease without therapies that alter disease progress and is currently managed with symptom-modifying therapies that are only modestly effective. We propose a randomized, sham-controlled clinical trial of pulsed low-intensity ultrasound (PLIUS) as a novel yet well-justified treatment that could fundamentally alter OA management. OA affects almost 27 million Americans with an estimated annual cost of over $80 billion. The prevalence of OA is increasing rapidly. Estimates suggest that about 60 million Americans will be affected by 2030. Still greater prevalence is seen in members of the armed services, making it a disease of special importance to the Department of Veterans Affairs. OA is the leading cause of lower extremity pain and disability in older age and is the leading indication for total knee replacement (TKR), with the number of TKR procedures having more than doubled over the last decade. The increasing burden of OA is largely because available medical management addresses only pain with long-term efficacy that is marginal at best. In spite of substantial progress in understanding the pathogenesis of OA, no effective disease modifying interventions have been established. Degenerative articular cartilage is central to the pathogenesis of OA, however, articular cartilage has limited capacity for repair. Thus, the development of OA therapeutics that focus on cartilage regeneration and repair strategies are of great importance. A large body of pre-clinical work has demonstrated the anabolic effect of mechanical stimulation on chondrocyte metabolism. Published literature from pre-clinical and clinical bone fracture and pre-clinical cartilage research indicate that effective mechanical stimulation can be delivered via PLIUS. These consistently positive data affirm the need to investigate the potential of PLIUS as an important intervention for treatment of OA. We propose a Phase IIa, multi-center, randomized, sham-controlled, parallel, double-blind trial with a prerandomization sham run-in period to determine if PLIUS is potentially more effective than sham as a symptom- and structure-modifying intervention in patients with early OA of the knee. PLIUS will be applied using an FDA-approved device already in clinical use for bone fracture healing. The study consists of three periods: a 28-day Screening Period, a four week Prerandomization Sham Run-in Period and a 48-Week Sham-controlled Treatment Period. The three recruiting centers, the Salt Lake City, Pittsburgh, and San Diego Veterans Affairs Medical Centers, have extensive experience in successfully conducting OA trials. Over a 23-month recruitment period, 178 patients with clinical and relatively early stage radiographic knee OA meeting entry criteria will be enrolled into the pre-randomization sham run- in period. A total of 160 patients who successfully completed the run-in period and continue to meet entry criteria will be randomized into the sham-controlled treatment period. All patients will be followed in the treatment period for 48 weeks, which is the time point for assessment of the co-primary outcomes of symptom relief, as assessed by the OMERACT-OARSI Responder Criteria, and structural modification, as assessed by MRI-determined medial femoral condyle cartilage thickness. Emerging data from the Osteoarthritis Initiative (OAI) suggests that this is a sensitive and specific measure for structural progression of OA. Innovative and exploratory disease markers, including subchondral bone marrow lesions and soluble serum and urine biomarkers for OA will also be evaluated, along with more traditional outcomes such as the WOMAC OA Index and radiographic joint space narrowing. The pre-clinical data supporting this study are described in the Research Plan. This project is a translational bench-to-bedside proposal targeting a highly debilitating, prevalent, and costly disease for which current treatment options are exceedingly limited. We have assembled an outstanding collaborative team of clinical scientists in leading OA centers within the Department of Veterans Affairs. If this intervention is successful and subsequently confirmed as an effective treatment for OA in a pivotal trial, it could fundamentally change the standard of care for this highly prevalent and debilitating disease, potentially improving the quality of life for tens of millions of veterans and other Americans.